Can nicotine receptor partial agonists, including varenicline and cytisine, help people to stop smoking

Cahill K, Stead LF, Lancaster T

Published Online:

February 16, 2011

When people stop smoking they experience cravings to smoke and unpleasant mood changes. Nicotine receptor partial agonists such as varenicline aim to reduce withdrawal symptoms and smoking satisfaction. We found 11 randomized controlled trials of varenicline compared with placebo. Three of these trials also included a direct comparison with bupropion. One other trial tested varenicline against placebo, as maintenance therapy for those who had recently quit with varenicline. Two further trials compared varenicline with nicotine patches. One trial gave varenicline to all participants, but varied the delivery of behavioural support. This trial is not included in the analyses, but contributes to the data on safety and tolerability. From these data, varenicline at standard dose increased the chances of quitting more than two-fold compared with placebo. Low-dose varenicline roughly doubled the chances of quitting, and reduced the number and severity of side effects. The number of people stopping smoking with varenicline was higher than with bupropion. The two trials with nicotine patches did not show a clear benefit of varenicline over the patches. The main side effect of varenicline was nausea, but this was mostly at mild or moderate levels and usually subsided over time. After the licensing phase, there were concerns that varenicline may be linked with depressed mood, agitation or suicidal thinking and behaviour in some smokers. Surveillance studies and further analyses of the trial data have not so far found strong support for this association.
The evidence on cytisine is limited at present, and no firm conclusions can yet be drawn about its effectiveness as an aid to quitting.

Abstract (click to read)

Background:

Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). Varenicline was developed as a nicotine receptor partial agonist from cytisine, a drug widely used in central and eastern Europe for smoking cessation. The first trial reports of varenicline were released in 2006, and further trials have now been published or are currently underway.

Objectives:

The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.

Search strategy:

We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or 'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH terms and free text, and we contacted authors of trial reports for additional information where necessary. The latest search was in September 2010.

Selection criteria:

We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment.

Data collection and analysis:

We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow up.

The main outcome measured was abstinence from smoking after at least six months from the beginning of treatment. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we performed meta-analysis to produce a risk ratio, using the Mantel-Haenszel fixed-effect model.

Main results:

We found 11 trials of varenicline compared with placebo for smoking cessation; three of these included a bupropion experimental arm. We also found one relapse prevention trial, comparing varenicline with placebo, and two open-label trials comparing varenicline with nicotine replacement therapy (NRT). We also include one trial in which all the participants were given varenicline, but received behavioural support either online or by phone calls, or by both methods. This trial is not included in the analyses, but contributes to the data on safety and tolerability. The included studies covered >10,300 participants, 6892 of whom used varenicline. We identified one trial of cytisine (Tabex) for inclusion.

The pooled risk ratio (RR) (10 trials, 4443 people, excluding one trial evaluating long term safety) for continuous abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.31 (95% confidence interval [CI] 2.01 to 2.66). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.09 (95% CI 1.56 to 2.78; 4 trials, 1272 people). The pooled RR for varenicline versus bupropion at one year was 1.52 (95% CI 1.22 to 1.88; 3 trials, 1622 people). The RR for varenicline versus NRT for point prevalence abstinence at 24 weeks was 1.13 (95% CI 0.94 to 1.35; 2 trials, 778 people). The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Post-marketing safety data raised questions about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation. The labelling of varenicline was amended in 2008, and the manufacturers produced a Medication Guide. Thus far, surveillance reports and secondary analyses of trial data lend little support to a causal relationship.

The one cytisine trial included in this review found that more participants taking cytisine stopped smoking compared with placebo at two-year follow up, with an RR of 1.61 (95% CI 1.24 to 2.08).

Authors' conclusions:

Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and threefold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion. Two open-label trials of varenicline versus NRT suggested a modest benefit of varenicline but confidence intervals did not rule out equivalence. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The main adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Possible links with serious adverse events, including depressed mood, agitation and suicidal thoughts, have been reported but are so far not substantiated.

There is a need for further independent community-based trials of varenicline, to test its efficacy and safety in smokers with varying co-morbidities and risk patterns. There is a need for further trials of the efficacy of treatment extended beyond 12 weeks. Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive.

This record should be cited as:

Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD006103. DOI: 10.1002/14651858.CD006103.pub5

Assessed as up to date:

October 30, 2010

Find the research

Get full text at The Cochrane Library

Primary Review Group:

Tobacco Addiction Group

PEARLS - Practical Evidence About Real Life Situations (click to read)

Clinical question:

How effective are nicotine receptor partial agonists for smoking cessation?

Bottom line:

Varenicline at standard dosage (1.0mg twice a day) increased the chances of successful long-term smoking cessation by more than two-fold compared with pharmacologically unassisted quit attempts. Varenicline at reduced dosage appeared to reduce the impact of adverse events in the early weeks of treatment and remained an effective aid to smoking cessation, delivering success rates similar to those achieved with nicotine replacement therapy (NRT) and bupropion. Limited evidence suggests varenicline may have a role to play in relapse prevention. The main adverse effect of varenicline was nausea, but mostly at mild to moderate levels, and this tended to subside over time.

Caveat:

Two open-label trials of varenicline versus NRT suggested a modest benefit for varenicline, but were inconclusive. Possible links with serious adverse events, including depressed mood, agitation and suicidal thoughts, have been reported but are so far not substantiated. Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive.

Context:

Varenicline was developed as a nicotine receptor partial agonist from cytisine, a drug widely used in central and eastern Europe for smoking cessation. Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine, to counteract withdrawal symptoms (acting as an agonist), and reducing smoking satisfaction (acting as an antagonist).

Cochrane Systematic Review:

Cahill K, Stead LF and Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Reviews, 2011, Issue 2. Article. No. CD006103. DOI: 10.1002/14651858. CD006103.pub4. This review contains 11 studies involving over 10,300 participants.

Authored by:

Brian R McAvoy

Cochrane Primary Health Care Field

Health topics:

Lungs & airways > Smoking cessation > Pharmacological interventions

Tobacco, drugs, & alcohol dependence > Tobacco > Pharmacological interventions

Cochrane Summaries^beta

Independent high-quality evidence for health care decision making

Can nicotine receptor partial agonists, including varenicline and cytisine, help people to stop smoking

More like this

Copyright © 2011 - The Cochrane Collaboration